Opioids are among the oldest drugs in existence, and remain a mainstay of pain management. Opium, the original opioid, is derived from poppy plants. “Opiates” are natural derivatives of opium, and include morphine, methadone, and heroin. “Opioids” are a broader class of drugs, that includes opium, opiates, and synthetic drugs with the same pharmacological effect of opium. Commonly used synthetic opioids include meperidine, fentanyl, alfentanil, sufentanil, and remifentanil.
Opioids are believed to exert their effects through binding of the mu receptor in the spinal cord and brain, and peripheral tissues. Binding at the mu receptor induces a wide variety of pharmacological effects, including therapeutic effects such as analgesia, effects which may be viewed as either side effects or therapeutic effects, depending on context, including sedation and decreased bowel motility, side effects such as nausea, vomiting, urinary retention, pruritis, ventilatory depression, addiction, and toxicity such as severe ventilatory depression, loss of consciousness and death.
Opioids differ from each other in many ways, including their route of delivery, their physicochemical composition, their drug absorption rate, their pharmacokinetics, and their pharmacodynamics. Noninvasive routes of opioid delivery include oral, rectal, transdermal, transmucosal, and via inhalation. Invasive routes of opioid delivery include intravenous, intramuscular, epidural, spinal, and by injection into joints. When injected intravenously, some opioids quickly enter the brain and spinal cord and thus have a very rapid onset of drug effect (e.g., alfentanil and remifentanil), while others are absorbed slowly to the site of action and have very slow onset of drug effect (e.g., morphine). Similarly, for some opioids the drug effect is very short-lived, owing to very rapid metabolism (e.g., remifentanil), while other opioids may have very slow metabolism and prolonged effect (e.g., methadone). In terms of pharmacodynamics, the potency of opioids covers nearly 5 orders of magnitude, from extraordinarily potent opioids such as carfentanil and etorphine (both used to stun elephants) to relatively less potent drugs such as methadone and morphine. The equivalent potencies of opioids (measured as a “therapeutic equivalence ratio”) are well established in the literature, and are often used when changing a patient's treatment regimen from one opioid to another.
Despite these differences, all opioids have the same potential to produce both profound levels of analgesia, and profound toxicity from hypoxia, which can be fatal. Because of the risk of hypoxia, physicians are reluctant to use appropriate doses of opioids to treat acute and chronic pain. As a result, hundreds of thousands of patients who could be provided better pain control receive inadequate doses of opioids. Conversely, even with an understandably cautious approach by the health care community to treatment of pain, every year, many patients die from opioid-induced ventilatory depression.
Pain is highly variable and highly subjective. Different patients respond differently to opioids. As a result, different patients need different amounts of analgesia to treat their pain. As such, it has become desirable to allow patients to vary the amount of analgesic they receive.
One attempt to better adjust opioid dosing in patients has been the introduction of “patient controlled analgesia” (“PCA”) (Ballantyne JC, et al. Postoperative patient-controlled analgesia: Meta-analyses of initial randomized control trials. J Clin Anesth 1993:5:182-193.) With the PCA system, the patient must be awake, and must activate a delivery mechanism to receive more opioid, before the drug is given. If the patient becomes overdosed from the opioid, then the patient will become unconscious and not request additional drug. In this manner, the PCA system uses a side effect of opioid, sedation, to limit the amount of opioid given. One problem with the PCA system is that the drug is injected rapidly after the patient requests it (typically, the time frame of administration of drug is under 1 minute) and because the drug most frequently used in the PCA is morphine, a drug that is slowly transferred from the plasma to the site of action—this results in a delay between the patient request for drug and the analgesic effect of the drug. As a result of this delay, patients often request a second (or third) dose of the drug while the opioid effect level of the first injection is still rising. PCA systems include a “lockout” period (commonly 5 minutes), which helps prevent patients from administering more opioid while the opioid drug effect is still rising. Lockout periods are typically controlled, defined or programmed by the health care provider, and there have been many instances where user error or inadvertence in programming the lockout period have resulted in the death of the patient. The patient also often feels frustrated by the lockout, as it diminishes the patients' control of dosing. Other disadvantages of the PCA include the invasive parenteral (intravenous) administration as well as the expensive infusion pumps thus restricting the use of the PCA to institutionalized patients.
A second attempt to better adjust opioid dosing in patients is in the self-administration of Nitrous Oxide during labour associated with childbirth. A nitrous oxide mask is held to the face by the patient during contractions, and is released from the face when adequate analgesia is achieved. However, this mechanism is a titration to analgesic effect and not used as a safety mechanism, since overdosing on nitrous oxide using this system of administration is not a significant concern. Furthermore, nitrous oxide is a gas which requires a heavy steel tank for storage and a complex delivery system for administration. Therefore, the use of nitrous oxide is primarily restricted to the hospital environment and not for ambulatory patients. An additional potential problem with nitrous oxide relates to its low potency and thus the necessity of administering a high concentration (more than 50%) of nitrous oxide in oxygen with a potential of a hypoxic mixture.
The current invention seeks to use two physiological responses of opioids: sedation and ventilatory depression, to limit the total dose of opioids that patients receive. In this manner, the invention seeks to increase safety of opioid drug delivery beyond what is currently accomplished with PCA or other existing opioid administration methods whereby only a single side effect is used to limit the exposure of patients to dangerously high levels of opioid drug effects. The invention also improves the use of sedation by removing the need for a “lockout” period, currently required in PCA systems, and removing the frustration and user error possible therein.